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Examining How the MAFB Transcription Factor Affects Islet β-Cell Function Postnatally.
Cyphert HA, Walker EM, Hang Y, Dhawan S, Haliyur R, Bonatakis L, Avrahami D, Brissova M, Kaestner KH, Bhushan A, Powers AC, Stein R
(2019) Diabetes 68: 337-348
MeSH Terms: Animals, Cells, Cultured, Chromatin Immunoprecipitation, Chromosomes, Artificial, Bacterial, DNA Methylation, Female, Humans, In Vitro Techniques, Insulin-Secreting Cells, Maf Transcription Factors, Large, MafB Transcription Factor, Mice, Mice, Transgenic, Pregnancy, Tryptophan Hydroxylase
Show Abstract · Added January 8, 2019
The sustained expression of the MAFB transcription factor in human islet β-cells represents a distinct difference in mice. Moreover, mRNA expression of closely related and islet β-cell-enriched MAFA does not peak in humans until after 9 years of age. We show that the MAFA protein also is weakly produced within the juvenile human islet β-cell population and that expression is postnatally restricted in mouse β-cells by de novo DNA methylation. To gain insight into how MAFB affects human β-cells, we developed a mouse model to ectopically express in adult mouse β-cells using transcriptional control sequences. Coexpression of MafB with MafA had no overt impact on mouse β-cells, suggesting that the human adult β-cell MAFA/MAFB heterodimer is functionally equivalent to the mouse MafA homodimer. However, MafB alone was unable to rescue the islet β-cell defects in a mouse mutant lacking MafA in β-cells. Of note, transgenic production of MafB in β-cells elevated tryptophan hydroxylase 1 mRNA production during pregnancy, which drives the serotonin biosynthesis critical for adaptive maternal β-cell responses. Together, these studies provide novel insight into the role of MAFB in human islet β-cells.
© 2018 by the American Diabetes Association.
1 Communities
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15 MeSH Terms
Gestational Diabetes Mellitus From Inactivation of Prolactin Receptor and MafB in Islet β-Cells.
Banerjee RR, Cyphert HA, Walker EM, Chakravarthy H, Peiris H, Gu X, Liu Y, Conrad E, Goodrich L, Stein RW, Kim SK
(2016) Diabetes 65: 2331-41
MeSH Terms: Animals, Cell Proliferation, Cells, Cultured, Cyclin A2, Cyclin B1, Cyclin B2, Cyclin D1, Cyclin D2, Diabetes, Gestational, Female, Forkhead Box Protein M1, Insulin, Insulin-Secreting Cells, MafB Transcription Factor, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Pregnancy, Receptors, Prolactin, Serotonin, Signal Transduction, Tryptophan Hydroxylase
Show Abstract · Added September 19, 2016
β-Cell proliferation and expansion during pregnancy are crucial for maintaining euglycemia in response to increased metabolic demands placed on the mother. Prolactin and placental lactogen signal through the prolactin receptor (PRLR) and contribute to adaptive β-cell responses in pregnancy; however, the in vivo requirement for PRLR signaling specifically in maternal β-cell adaptations remains unknown. We generated a floxed allele of Prlr, allowing conditional loss of PRLR in β-cells. In this study, we show that loss of PRLR signaling in β-cells results in gestational diabetes mellitus (GDM), reduced β-cell proliferation, and failure to expand β-cell mass during pregnancy. Targeted PRLR loss in maternal β-cells in vivo impaired expression of the transcription factor Foxm1, both G1/S and G2/M cyclins, tryptophan hydroxylase 1 (Tph1), and islet serotonin production, for which synthesis requires Tph1. This conditional system also revealed that PRLR signaling is required for the transient gestational expression of the transcription factor MafB within a subset of β-cells during pregnancy. MafB deletion in maternal β-cells also produced GDM, with inadequate β-cell expansion accompanied by failure to induce PRLR-dependent target genes regulating β-cell proliferation. These results unveil molecular roles for PRLR signaling in orchestrating the physiologic expansion of maternal β-cells during pregnancy.
© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
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23 MeSH Terms
Stress-impaired transcription factor expression and insulin secretion in transplanted human islets.
Dai C, Kayton NS, Shostak A, Poffenberger G, Cyphert HA, Aramandla R, Thompson C, Papagiannis IG, Emfinger C, Shiota M, Stafford JM, Greiner DL, Herrera PL, Shultz LD, Stein R, Powers AC
(2016) J Clin Invest 126: 1857-70
MeSH Terms: Animals, Gene Expression Regulation, Heterografts, Homeodomain Proteins, Humans, Insulin-Secreting Cells, Islets of Langerhans Transplantation, MafB Transcription Factor, Mice, Mice, Knockout
Show Abstract · Added April 12, 2016
Type 2 diabetes is characterized by insulin resistance, hyperglycemia, and progressive β cell dysfunction. Excess glucose and lipid impair β cell function in islet cell lines, cultured rodent and human islets, and in vivo rodent models. Here, we examined the mechanistic consequences of glucotoxic and lipotoxic conditions on human islets in vivo and developed and/or used 3 complementary models that allowed comparison of the effects of hyperglycemic and/or insulin-resistant metabolic stress conditions on human and mouse islets, which responded quite differently to these challenges. Hyperglycemia and/or insulin resistance impaired insulin secretion only from human islets in vivo. In human grafts, chronic insulin resistance decreased antioxidant enzyme expression and increased superoxide and amyloid formation. In human islet grafts, expression of transcription factors NKX6.1 and MAFB was decreased by chronic insulin resistance, but only MAFB decreased under chronic hyperglycemia. Knockdown of NKX6.1 or MAFB expression in a human β cell line recapitulated the insulin secretion defect seen in vivo. Contrary to rodent islet studies, neither insulin resistance nor hyperglycemia led to human β cell proliferation or apoptosis. These results demonstrate profound differences in how excess glucose or lipid influence mouse and human insulin secretion and β cell activity and show that reduced expression of key islet-enriched transcription factors is an important mediator of glucotoxicity and lipotoxicity.
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10 MeSH Terms
The MAFB transcription factor impacts islet α-cell function in rodents and represents a unique signature of primate islet β-cells.
Conrad E, Dai C, Spaeth J, Guo M, Cyphert HA, Scoville D, Carroll J, Yu WM, Goodrich LV, Harlan DM, Grove KL, Roberts CT, Powers AC, Gu G, Stein R
(2016) Am J Physiol Endocrinol Metab 310: E91-E102
MeSH Terms: Adolescent, Adult, Animals, Biomarkers, Female, Humans, Insulin-Secreting Cells, Islets of Langerhans, Macaca mulatta, MafB Transcription Factor, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Primates, Rodentia, Young Adult
Show Abstract · Added February 6, 2016
Analysis of MafB(-/-) mice has suggested that the MAFB transcription factor was essential to islet α- and β-cell formation during development, although the postnatal physiological impact could not be studied here because these mutants died due to problems in neural development. Pancreas-wide mutant mice were generated to compare the postnatal significance of MafB (MafB(Δpanc)) and MafA/B (MafAB(Δpanc)) with deficiencies associated with the related β-cell-enriched MafA mutant (MafA(Δpanc)). Insulin(+) cell production and β-cell activity were merely delayed in MafB(Δpanc) islets until MafA was comprehensively expressed in this cell population. We propose that MafA compensates for the absence of MafB in MafB(Δpanc) mice, which is supported by the death of MafAB(Δpanc) mice soon after birth from hyperglycemia. However, glucose-induced glucagon secretion was compromised in adult MafB(Δpanc) islet α-cells. Based upon these results, we conclude that MafB is only essential to islet α-cell activity and not β-cell. Interestingly, a notable difference between mice and humans is that MAFB is coexpressed with MAFA in adult human islet β-cells. Here, we show that nonhuman primate (NHP) islet α- and β-cells also produce MAFB, implying that MAFB represents a unique signature and likely important regulator of the primate islet β-cell.
1 Communities
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18 MeSH Terms
Islet-enriched gene expression and glucose-induced insulin secretion in human and mouse islets.
Dai C, Brissova M, Hang Y, Thompson C, Poffenberger G, Shostak A, Chen Z, Stein R, Powers AC
(2012) Diabetologia 55: 707-18
MeSH Terms: Adolescent, Adult, Animals, Female, Gene Expression Profiling, Gene Expression Regulation, Homeodomain Proteins, Humans, Hyperglycemia, Insulin, Insulin Secretion, Islets of Langerhans, MafB Transcription Factor, Male, Mice, Mice, Inbred Strains, Middle Aged, Phosphodiesterase Inhibitors, Protein Transport, RNA, Messenger, Secretory Pathway, Species Specificity, Tissue Culture Techniques, Trans-Activators, Young Adult
Show Abstract · Added December 5, 2013
AIMS/HYPOTHESIS - Our understanding of the transcription factors that control the development and function of rodent islet beta cells is advancing rapidly, yet less is known of the role they play in similar processes in human islets.
METHODS - To characterise the abundance and regulation of key proteins involved in glucose-regulated insulin secretion in human islets, we examined the expression of MAFA, MAFB, GLUT2 (also known as SLC2A2), βGK (also known as GCK) and PDX1 in isolated, highly purified human islets with an intact insulin secretory pattern. We also assessed these features in islets from two different mouse strains (C57BL/6J and FVB).
RESULTS - Compared with mouse islets, human islets secreted more insulin at baseline glucose (5.6 mmol/l), but less upon stimulation with high glucose (16.7 mmol/l) or high glucose plus 3-isobutyl-1-methyl-xanthine. Human islets had relatively more MAFB than PDX1 mRNA, while mouse islets had relatively more Pdx1 than Mafb mRNA. However, v-maf musculoaponeurotic fibrosarcoma oncogene homologue (MAF) B protein was found in human islet alpha and beta cells. This is unusual as this regulator is only produced in islet alpha cells in adult mice. The expression of insulin, MAFA, βGK and PDX1 was not glucose-regulated in human islets with an intact insulin secretory pattern.
CONCLUSIONS/INTERPRETATION - Our results suggest that human islets have a distinctive distribution and function of key regulators of the glucose-stimulated insulin secretion pathway, emphasising the urgent need to understand the processes that regulate human islet beta cell function.
3 Communities
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25 MeSH Terms
MafA and MafB regulate genes critical to beta-cells in a unique temporal manner.
Artner I, Hang Y, Mazur M, Yamamoto T, Guo M, Lindner J, Magnuson MA, Stein R
(2010) Diabetes 59: 2530-9
MeSH Terms: Aging, Animals, Embryonic Development, Gene Expression Regulation, Developmental, Glucagon, Glucose-6-Phosphatase, Insulin, Insulin-Secreting Cells, Maf Transcription Factors, Large, MafB Transcription Factor, Mice, Oligonucleotide Array Sequence Analysis, Proteins, RNA, RNA, Messenger, Retinol-Binding Proteins, Plasma, Reverse Transcriptase Polymerase Chain Reaction, Up-Regulation
Show Abstract · Added January 12, 2012
OBJECTIVE - Several transcription factors are essential to pancreatic islet β-cell development, proliferation, and activity, including MafA and MafB. However, MafA and MafB are distinct from others in regard to temporal and islet cell expression pattern, with β-cells affected by MafB only during development and exclusively by MafA in the adult. Our aim was to define the functional relationship between these closely related activators to the β-cell.
RESEARCH DESIGN AND METHODS - The distribution of MafA and MafB in the β-cell population was determined immunohistochemically at various developmental and perinatal stages in mice. To identify genes regulated by MafB, microarray profiling was performed on wild-type and MafB(-/-) pancreata at embryonic day 18.5, with candidates evaluated by quantitative RT-PCR and in situ hybridization. The potential role of MafA in the expression of verified targets was next analyzed in adult islets of a pancreas-wide MafA mutant (termed MafA(ΔPanc)).
RESULTS - MafB was produced in a larger fraction of β-cells than MafA during development and found to regulate potential effectors of glucose sensing, hormone processing, vesicle formation, and insulin secretion. Notably, expression from many of these genes was compromised in MafA(ΔPanc) islets, suggesting that MafA is required to sustain expression in adults.
CONCLUSIONS - Our results provide insight into the sequential manner by which MafA and MafB regulate islet β-cell formation and maturation.
3 Communities
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18 MeSH Terms
Phosphorylation within the MafA N terminus regulates C-terminal dimerization and DNA binding.
Guo S, Vanderford NL, Stein R
(2010) J Biol Chem 285: 12655-61
MeSH Terms: Animals, Cell Differentiation, DNA, HeLa Cells, Humans, Maf Transcription Factors, Large, MafB Transcription Factor, Mice, Phosphorylation, Protein Binding, Protein Multimerization, Protein Processing, Post-Translational, Protein Structure, Tertiary, Recombinant Fusion Proteins
Show Abstract · Added March 7, 2014
Phosphorylation regulates transcription factor activity by influencing dimerization, cellular localization, activation potential, and/or DNA binding. Nevertheless, precisely how this post-translation modification mediates these processes is poorly understood. Here, we examined the role of phosphorylation on the DNA-binding properties of MafA and MafB, closely related transcriptional activators of the basic-leucine zipper (b-Zip) family associated with cell differentiation and oncogenesis. Many common phosphorylation sites were identified by mass spectrometry. However, dephosphorylation only precluded the detection of MafA dimers and consequently dramatically reduced DNA-binding ability. Analysis of MafA/B chimeras revealed that sensitivity to the phosphorylation status of MafA was imparted by sequences spanning the C-terminal dimerization region (amino acids (aa) 279-359), whereas the homologous MafB region (aa 257-323) conveyed phosphorylation-independent DNA binding. Mutational analysis showed that formation of MafA dimers capable of DNA binding required phosphorylation within the distinct N-terminal transactivation domain (aa 1-72) and not the C-terminal b-Zip region. These results demonstrate a novel relationship between the phosphoamino acid-rich transactivation and b-Zip domains in controlling MafA DNA-binding activity.
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14 MeSH Terms
MafA is a dedicated activator of the insulin gene in vivo.
Artner I, Hang Y, Guo M, Gu G, Stein R
(2008) J Endocrinol 198: 271-9
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Chick Embryo, DNA, Electroporation, Endoderm, Glucagon, HeLa Cells, Humans, Immunohistochemistry, Insulin, Islets of Langerhans, Maf Transcription Factors, MafB Transcription Factor, Mice, Nerve Tissue Proteins, Promoter Regions, Genetic, Protein Binding, Protein Multimerization, Reverse Transcriptase Polymerase Chain Reaction
Show Abstract · Added February 3, 2014
As successful generation of insulin-producing cells could be used for diabetes treatment, a concerted effort is being made to understand the molecular programs underlying islet beta-cell formation and function. The closely related MafA and MafB transcription factors are both key mammalian beta-cell regulators. MafA and MafB are co-expressed in insulin+beta-cells during embryogenesis, while in the adult pancreas only MafA is produced in beta-cells and MafB in glucagon+alpha-cells. MafB-/- animals are also deficient in insulin+ and glucagon+ cell production during embryogenesis. However, only MafA over-expression selectively induced endogenous Insulin mRNA production in cell line-based assays, while MafB specifically promoted Glucagon expression. Here, we analyzed whether these factors were sufficient to induce insulin+ and/or glucagon+ cell formation within embryonic endoderm using the chick in ovo electroporation assay. Ectopic expression of MafA, but not MafB, promoted Insulin production; however, neither MafA nor MafB were capable of inducing Glucagon. Co-electroporation of MafA with the Ngn3 transcription factor resulted in the development of more organized cell clusters containing both insulin- and glucagon-producing cells. Analysis of chimeric proteins of MafA and MafB demonstrated that chick Insulin activation depended on sequences within the MafA C-terminal DNA-binding domain. MafA was also bound to Insulin and Glucagon transcriptional control sequences in mouse embryonic pancreas and beta-cell lines. Collectively, these results demonstrate a unique ability for MafA to independently activate Insulin transcription.
1 Communities
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20 MeSH Terms
The islet beta cell-enriched MafA activator is a key regulator of insulin gene transcription.
Zhao L, Guo M, Matsuoka TA, Hagman DK, Parazzoli SD, Poitout V, Stein R
(2005) J Biol Chem 280: 11887-94
MeSH Terms: Basic Helix-Loop-Helix Transcription Factors, DNA-Binding Proteins, Gene Expression Regulation, HeLa Cells, Homeodomain Proteins, Humans, Insulin, Islets of Langerhans, Maf Transcription Factors, Large, MafB Transcription Factor, Nuclear Proteins, Oncogene Proteins, Trans-Activators, Transcription Factors, Transcription, Genetic
Show Abstract · Added December 10, 2013
The islet-enriched MafA, PDX-1, and BETA2 activators contribute to both beta cell-specific and glucose-responsive insulin gene transcription. To investigate how these factors impart activation, their combined impact upon insulin enhancer-driven expression was first examined in non-beta cell line transfection assays. Individual expression of PDX-1 and BETA2 led to little or no activation, whereas MafA alone did so modestly. MafA together with PDX-1 or BETA2 produced synergistic activation, with even higher insulin promoter activity found when all three proteins were present. Stimulation was attenuated upon compromising either MafA transactivation or DNA-binding activity. MafA interacted with endogenous PDX-1 and BETA2 in coimmunoprecipitation and in vitro GST pull-down assays, suggesting that regulation involved direct binding. Dominant-negative acting and small interfering RNAs of MafA also profoundly reduced insulin promoter activity in beta cell lines. In addition, MafA was induced in parallel with insulin mRNA expression in glucose-stimulated rat islets. Insulin mRNA levels were also elevated in rat islets by adenoviral-mediated expression of MafA. Collectively, these results suggest that MafA plays a key role in coordinating and controlling the level of insulin gene expression in islet beta cells.
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15 MeSH Terms
Members of the large Maf transcription family regulate insulin gene transcription in islet beta cells.
Matsuoka TA, Zhao L, Artner I, Jarrett HW, Friedman D, Means A, Stein R
(2003) Mol Cell Biol 23: 6049-62
MeSH Terms: Amino Acid Sequence, Animals, Avian Proteins, Binding Sites, Cells, Cultured, DNA-Binding Proteins, Enhancer Elements, Genetic, Gene Expression Regulation, Homeodomain Proteins, Humans, Hydrogen-Ion Concentration, Insulin, Islets of Langerhans, Lectins, C-Type, Macromolecular Substances, Maf Transcription Factors, Large, MafB Transcription Factor, Mass Spectrometry, Mice, Molecular Sequence Data, Multigene Family, Nuclear Proteins, Oncogene Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-maf, Receptors, Immunologic, Sequence Homology, Amino Acid, Trans-Activators, Transcription Factors, Transcription, Genetic
Show Abstract · Added December 10, 2013
The C1/RIPE3b1 (-118/-107 bp) binding factor regulates pancreatic-beta-cell-specific and glucose-regulated transcription of the insulin gene. In the present study, the C1/RIPE3b1 activator from mouse beta TC-3 cell nuclear extracts was purified by DNA affinity chromatography and two-dimensional gel electrophoresis. C1/RIPE3b1 binding activity was found in the roughly 46-kDa fraction at pH 7.0 and pH 4.5, and each contained N- and C-terminal peptides to mouse MafA as determined by peptide mass mapping and tandem spectrometry. MafA was detected in the C1/RIPE3b1 binding complex by using MafA peptide-specific antisera. In addition, MafA was shown to bind within the enhancer region (-340/-91 bp) of the endogenous insulin gene in beta TC-3 cells in the chromatin immunoprecipitation assay. These results strongly suggested that MafA was the beta-cell-enriched component of the RIPE3b1 activator. However, reverse transcription-PCR analysis demonstrated that mouse islets express not only MafA but also other members of the large Maf family, specifically c-Maf and MafB. Furthermore, immunohistochemical studies revealed that at least MafA and MafB were present within the nuclei of islet beta cells and not within pancreas acinar cells. Because MafA, MafB, and c-Maf were each capable of specifically binding to and activating insulin C1 element-mediated expression, our results suggest that all of these factors play a role in islet beta-cell function.
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30 MeSH Terms